抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Dye-sensitized solar cells (DSCs) offer the possibilities to design solar cells with a large flexibility in shape, color, and transparency. DSC research groups have been established around the worl ...

/pdf/dye-sensitized-solar-cells-50b0w2bhsr.pdf

Dye-Sensitized Solar Cells

2.3. Evaluation of Photocatalytic Water Splitting 6507 2.3.1. Photocatalytic Activity 6507 2.3.2. Photocatalytic Stability 6507 3. UV-Active Photocatalysts for Water Splitting 6507 3.1. d0 Metal Oxide Photocatalyts 6507 3.1.1. Ti-, Zr-Based Oxides 6507 3.1.2. Nb-, Ta-Based Oxides 6514 3.1.3. W-, Mo-Based Oxides 6517 3.1.4. Other d0 Metal Oxides 6518 3.2. d10 Metal Oxide Photocatalyts 6518 3.3. f0 Metal Oxide Photocatalysts 6518 3.4. Nonoxide Photocatalysts 6518 4. Approaches to Modifying the Electronic Band Structure for Visible-Light Harvesting 6519

Semiconductor-based Photocatalytic Hydrogen Generation

AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore

PL02-05 

All cancers are due to abnormalities in DNA. The availability of the human genome sequence has led to the proposal that resequencing of cancer genomes will reveal the full complement of somatic mutations and hence all the cancer genes. To explore the nature of the information that will be derived from cancer genome sequencing we have sequenced the coding exons of the family of 518 protein kinases, ~1.3Mb DNA per cancer sample, in 210 cancers of diverse histological types. Despite the screen being directed toward the coding regions of a gene family that has previously been strongly implicated in oncogenesis, the results indicate that the majority of somatic mutations detected are “passengers”. There is considerable variation in the number and pattern of these mutations between individual cancers, indicating substantial diversity of processes of molecular evolution between cancers. The imprints of exogenous mutagenic exposures, mutagenic treatment regimes and DNA repair defects can all be seen in the distinctive mutational signatures of individual cancers. This systematic mutation screen and others have previously yielded a number of cancer genes that are frequently mutated in one or more cancer types and which are now anticancer drug targets (for example BRAF , PIK3CA , and EGFR ). However, detailed analyses of the data from our screen additionally suggest that there exist a large number of additional “driver” mutations which are distributed across a substantial number of genes. It therefore appears that cells may be able to utilise mutations in a large repertoire of potential cancer genes to acquire the neoplastic phenotype. However, many of these genes are employed only infrequently. These findings may have implications for future anticancer drug development.

Patterns of Somatic Mutation in Human Cancer Genomes

中枢神経系疾患の治療は正常細胞（ニューロン）の機能維持を目的とするが，脳血管障害のように機能障害の原因が細胞の死滅に基づくことは多い．一方，脳腫瘍の治療においては薬物療法や放射線療法といった腫瘍細胞の死滅を目標とするものが大きな位置を占める．いずれの場合にも，細胞死の機序を理解することは各種病態や治療法の理解のうえで重要である．現在のところ最も研究の進んでいる細胞死の型はアポトーシスである．そのなかで重要な位置を占めるミトコンドリアにおける反応および抗アポトーシス因子について概要を紹介する．

Neuroscience 細胞死：最近の知見

Several interaction modes of glycine with one Zn + or Zn 2+ and further with one and even two H 2 O molecules in the gas phase are studied at the hybrid three-parameter B3LYP and Hartree–Fock level, respectively. On the basis of these optimized geometries, single point calculations are performed using different theoretical methods and larger basis sets. The calculated results imply that the most stable glycine- Zn + isomer is a five-membered ring with Zn + bound to both amino nitrogen and carbonyl oxygen (NO) of glycine, and the next most stable glycine- Zn + species is a four-membered ring with Zn + coordinated at both oxygen ends (OO) of the zwitterionic glycine. The binding energy of the most stable glycine- Zn + is 68.5 kcal/mol calibrated at the BHLYP/6-311+G*//6-311+G* level. On the contrary with glycine- Zn + isomers, the most stable glycine- Zn 2+ species holds the similar coordination mode to that of next most stable glycine- Zn 2+ complex, while the next most stable glycine- Zn 2+ exhibits the similar coordination mode to that of the most stable glycine- Zn + . The binding strength of these glycine- Zn 2+ isomers are all far more than those of their corresponding counterparts of glycine- Zn + isomers, such as the binding energy of the most stable glycine- Zn 2+ being 234.4 kcal/mol, showing stronger electrostaticinteraction. The reoptimization for the two most stable modes with the different valent states (+1,+2) to combine a H 2 O molecule at their each end of Zn ion show that the relative energy ordering does not change, and also resembles their no- H 2 O -combined counterparts. However, an interesting and important observation has been first obtained that single hydration effect can strikingly strengthen the stability of the monovalent OO form though it is still higher by 0.1 kcal/mol in energy than the NO counterpart. Hydration effect of double waters can reverse their relative stability due to the strong hydrogen bond effect in the OO form. Different from the case of the two monovalent hydrated complexes, calculated results for the divalent zinc ion chelated complexes show that with or without single hydration hardly change the value of their relative energy, and hydration strength and glycine deformation difference induced with or without hydration in the two different modes display surprising similarity. So we predict that the further hydration basically do not yield any effect on the relative stability. The prediction for the hydration effect on the glycine- Zn + /Zn 2+ system would be also suitable for its analogs, such as glycine- Cu + /Cu 2+ and glycine- Ni + /Ni 2+ systems, and even suitable for other similar transition metal ion-chelated glycine systems.

Glycine-Zn+/Zn2+ and their hydrates: On the number of water molecules necessary to stabilize the switterionic glycine-Zn+/Zn2+ over the nonzwitterionic ones

Investigation of the internal conversion time of the chlorophyll a from S3, S2 to S1

ion. This is followed by the rebound of oxygen to form a normal gem-diol intermediate, and subsequent dehydration of the gem-diol to give the acetaldehyde product. The other mechanism is the dual hydrogen abstraction (DHA) mechanism (Scheme 1B). It also starts with the rate-determining H-abstraction from the a carbon, followed by a second H-abstraction from the hydroxyl group of the ethanoyl radical, and formation of the aldehyde product. Recently, Guengerich and Ortiz de Montellano et al. reported that the active site of human CYP2E1 is sterically unhindered directly above the iron for a distance of about 10 =. This means that several ethanol molecules and various binding modes might exist, which lead to mechanisms other than those shown in Scheme 1A and B. Moreover, in the cholesterol side-chain cleavage reaction, CYP450 has been proposed to perform dual hydrogen abstraction from two hydroxyl groups, which could results in the C20 C22 bond cleavage. In line with this evidence, we present here an alternative mechanism in addition to the aforementioned two, called the “reversed dual hydrogen abstraction” (R-DHA) mechanism (Scheme 1C). The key difference between the normal DHA mechanism and R-DHA is the reversed sequence of H-abstraction events. Density functional theoretical calculations (see Computational Methods Section) were carried out on these three mechanisms. Since the electronic ground state of compound I—the active species of CYP450—is a set of nearly degenerate low-spin (LS) doublet and high-spin (HS) quartet states, many of the reactions mediated by this enzyme involve two-state reactivity. Accordingly, the three mechanisms were explored on both spin-state surfaces. Our calculated results revealed that the polarity of the heme pocket is important for mechanistic selection. Bulk polarity effect causes the R-DHA mechanism to be the predominant one in a polar environment, while in a traditional nonpolar protein environment, oxidation proceeds competitively in both the gem-diol and R-DHA mechanisms. Extended studies revealed that this mechanistic switch might relate to one of the most significant roles of CYP2E1: that it can adapt its ethanol metabolism in response to increasing blood ethanol level. To the best of our knowledge, this study provides the first theoretical insights into the mechanistic details of alcohol oxidation mediated by CYP450. Figure 1 shows the energy profiles for the gem-diol mechanism, in which a hydrogen atom is abstracted from Ca [a] Y. Wang, Prof. C. Yang , Dr. H. Wang, Prof. K. Han State Key Laboratory of Molecular Reaction Dynamics Dalian Institute of Chemical Physics, Chinese Academy of Sciences Dalian 116023 (China) Fax: (+86)411-84675584 E-mail : klhan@dicp.ac.cn [b] Prof. S. Shaik Institute of Chemistry and the Lise Meitner-Minerva Center for Computational Quantum Chemistry, The Hebrew University of Jerusalem 91904 Jerusalem (Israel) Fax: (+972)2-658-4680 E-mail : sason@yfaat.ch.huji.ac.il [c] Prof. C. Yang , Prof. K. Han Department of Physics, Ludong University Yantai 264025 (China) Supporting information for this article is available on the WWW under http://www.chembiochem.org or from the author. Scheme 1. Three mechanistic hypotheses for ethanol oxidation by CYP2E1. ChemBioChem 2007, 8, 277 – 281 E 2007 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim 277 (Scheme 1A). Initially, H-abstraction occurs both on the HS and LS routes. This is the rate-determining step, and the activation energies are about 11.7/10.3 kcalmol 1 for the quartet/doublet states. Because the C H bond of ethanol is weaker than the normal alkane and the resulting radical is a better electron donor, the subsequent radical-rebound process is barrier free. This leads to the formation of the gem-diol complexes in a concerted mechanism. The latter complexes, in turn, eliminate a water molecule and generate acetaldehyde and the ferric-aqua complex. As shown in Scheme 2, when the rotation of FeOH is coupled with the rotation of the enol radical, the intermediate, IM, will generate the acetaldehyde complex (PC) directly through the normal DHA mechanism (Scheme 1B). Inspection of Figure 1 shows that the rate-determining H-abstraction barriers increase by 1.4–2.5 kcalmol 1 when bulk polarity corrections of the hydrophobic heme pocket of CYP2E1 are added (by using an environment with low polarity, e=5.62). In a relatively polar environment (with an appropriate dielectric constant, e= 24.55) the bulk polarity corrections further raise these barriers by 0.1–1.1 kcalmol . By taking zero-point energy (ZPE) corrections into account, the barriers (relative to the corresponding RCs) become 13.2/ 14.4 kcalmol 1 for the quartet/doublet states, respectively. Figure 2 shows the energy profile for the R-DHA mechanism in which H-abstraction occurs from the hydroxyl group (Scheme 1C). Note the differences in the structures of the reactants complex (RC) in Figure 2 compared with the one in Figure 1. The Habstraction from the OH group leads to an activation barrier of 12.3/12.9 kcalmol 1 for the quartet/doublet states, and generates the corresponding radical intermediates, IM (Table S4 in the Supporting Information). From the IM the two spin-state surfaces bifurcate in the second H-abstraction step, in which PorFe OH(SH) abstracts a hydrogen atom from Ca. The H-abstraction capability of the Fe OH complex in IM intermediates was demonstrated recently. Furthermore, in the present case, the C OC group in the ethanoyl radical weakens the Ca H bond and thereby greatly facilitates the second H-abstraction step. However, there is now a significant difference between the two spin states, which arises due to the unique electronic structure of the PorFe OH(SH) moiety (Figure 3). During H-abstraction, an electron shifts from the occupied sC H orbital of the enthanoyl radical to a virtual orbital, either to p* xz or s* z2 , of the PorFe OH(SH) complex. For the doublet state, the electron shifts from the sC H orbital to the low-lying p* xz ( 0.115 a.u.) orbital. By contrast, in order to conserve the spin in the quartet state, the electron must transfer from sC H to the high-lying s*z2 ( 0.087 a.u.) orbital. Hence, the second H-abstraction on the HS route has a significant barrier—much more so than on the LS route. As such, in the HS route, the energy of TS2 for H-abstraction from Ca is 2.2 kcalmol 1 higher than that of TS1. By contrast, in the LS route, TS2 lies 3.0 kcalmol 1 below TS1; therefore, it is the first H-abstraction step that would be rate limiting unless spin flip can occur. Indeed, the spin-orbital coupling (SOC) of the two closely lying spin states of PorFeOH/CH3CH2OC en route to the second TS, is significant and will mediate transitions from the HS route to the LS route. Consequently, H-abstraction from the hydroxyl group of ethanol will be the rate-limiting step for the R-DHA mechanism. The H-abstraction barriers decrease by 0.0– Figure 1. UB3LYP/LACV3P+ */LACVP** energy profile (in kcalmol ) for ethanol oxidation by compound I of CYP2E1 in the gem-diol mechanism. The relative energies include zero-point energy corrections and correspond to: gas phase (no parentheses), a weakpolar medium (e=5.62; in parenthesis), and a polar medium (e=24.55; in square brackets). RC: reactants complex; IM: intermediate; PC: acetaldehyde complex; TS: transition state?. Scheme 2. The OH group and enol radical rotations of the radical intermediates lead to the formation of gem-diol (in the gem-diol mechanism) and formaldehyde (in the normal DHA mechanism) complexes; IM: intermediate. 278 www.chembiochem.org E 2007 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim ChemBioChem 2007, 8, 277 – 281 0.9 kcalmol 1 when the hydrophobic protein environment effect is incorporated (e=5.7). The bulk polarity corrections of a relatively polar environment (when using an appropriate dielectric constant, e=24.55) further decreases these barriers by 0.6–0.9 kcalmol . After the incorporation of ZPE corrections the barriers (relative to the corresponding RCs) become 11.7/ 11.1 kcalmol 1 for the quartet/doublet states, respectively. Comparison of the results of the two mechanisms in Figures 1 and 2 reveals that in the gas phase the activation energy of the rate-determining H-abstraction in the gem-diol mechanism is about 2.0 kcalmol 1 lower than the R-DHA mechanism. However, when the bulk polarity effect of the hydrophobic heme pocket of CYP2E1 is taken into account, the energy barrier for H-abstraction in the gem-diol mechanism becomes 1.3 kcalmol 1 higher than the R-DHA mechanism. In a relatively polar environment (dielectric constant, e=24.55) the calculated results show that the barriers for the R-DHA mechanism drop to 11.1– 11.7 kcalmol , while those for the gem-diol mechanism rise to 13.2–14.4 kcalmol . Therefore, in a polar environment (e=24.55) the barriers of the R-DHA mechanism are lower than those in the gem-diol mechanism by 2.1 kcalmol . Consequently, the oxidation of ethanol to acetaldehyde is predicted to proceed predominantly by the R-DHA mechanism. The calculated kinetic isotope effects (KIEs) are 5.8/ 5.9 for the doublet/quartet states of the gem-diol mechanism, and 2.2/3.9 (doublet/quartet) for the RDHA mechanism. The KIEs for the latter mechanism refer to the second step in Figure 2 for H-abstraction from the methylene group of the CH3CH2OC radical. The experimental data revealed a KIE value (3.8) between that of the gem-diol and R-DHA mechanisms, which is in line with the competitive gem-diol/R-DHA mechanisms. In conclusion, the calculated results show that the new R-DHA mechanism competes with the traditional gem-diol mechanism in a weak polar environment (e= 5.62), which reflects the hydrophobic heme pocket of CYP2E1. When the bulk polarity of the heme pocket is more polar (e= 24.55) the new R-DHA mechanism predominates. We then applied this mechanistic finding to explain the most significant role of CYP2E1, that is, its adaptive response to high blood et

Ke-Li Han

Papers

Glycine-Zn+/Zn2+ and their hydrates: On the number of water molecules necessary to stabilize the switterionic glycine-Zn+/Zn2+ over the nonzwitterionic ones

Investigation of the internal conversion time of the chlorophyll a from S3, S2 to S1

A new mechanism for ethanol oxidation mediated by cytochrome P450 2E1: bulk polarity of the active site makes a difference.

Nonadiabatic effects in D+ + H2 and H+ + D2

Anion-Exchange-Triggered 1,3-Shift of an NH Proton to Iridium in Protic N-Heterocyclic Carbenes: Hydrogen-Bonding and Ion-Pairing Effects